Physiological and molecular metabolic consequences of fetal hyperglycernia

当发育中的胎儿暴露在高水平的葡萄糖中时，就会发生胎儿高血糖。例如 在人类中，当母亲患有糖尿病时就是这种情况。胎儿高血糖与健康有关 胎儿的并发症，包括先兆子痫、胎儿巨大儿，甚至胎儿死亡。此外, 胎儿高血糖还会增加个体在以后的生活中患上各种疾病的风险。 暴露在胎儿高血糖环境中的成年人更容易肥胖、胰岛素抵抗、2型糖尿病、 心血管疾病和几种代谢综合征。到目前为止，生理和分子方面的 胎儿高血糖和成人后遗症之间的联系机制很差。 明白了。这项计划的中心目标是检查生理和分子基础。 仅在胚胎发育期间暴露于高水平葡萄糖的成年人的代谢性疾病。要完成 为了实现这一目标，我们最近建立了一种斑马鱼胎儿高血糖模型。斑马鱼提供了几种 完成这一项目的优势。从生物学角度来看，斑马鱼胚胎具有独特的 “封闭系统”的特征，即在发育的头5天，胚胎完全依赖于 母体在排卵期间储存的卵黄囊，与母体之间不发生能量交换 胚胎发育结束前的外部世界。因此，在斑马鱼中，我们可以直接暴露胚胎 到已知浓度的葡萄糖。因此，特定目标1将检验胎儿高血糖的假设 导致喂食正常饮食的成年人的BMI、脂肪量和胰岛素抵抗增加。特定目标2将 验证胚胎高血糖增加糖酵解同时减少􀈕氧化的假说 在胚胎和成人体内。具体目标3将检验胎儿高血糖引起的假说 成人高脂血症和非酒精性脂肪性肝病。具体目标4将检验这样的假设 胚胎高血糖会增加循环中的血脂水平，并在以后的生活中导致动脉粥样硬化。 成功完成这项建议将导致更好地理解生理和 胎儿高血糖的分子后果，将有助于确定战略性治疗 预防长期接触葡萄糖成人发生代谢性疾病的干预措施 胚胎发生。

Fetal hyperglycemia occurs when the developing fetus is exposed to high levels of glucose. For example in humans, this is the case when the mother has diabetes. Fetal hyperglycemia is linked to health complications for the fetus, including preeclamsia, fetal macrosomia and even fetal death. In addition, fetal hyperglycemia also increases the risk for the individual to develop a variety of diseases later in life. Adults exposed to fetal hyperglycemia are more susceptible to obesity, insulin resistance, type 2 diabetes, cardiovascular diseases and several metabolic syndromes. To date, the physiological and molecular mechanisms that underlie the link between fetal hyperglycemia and the adult sequelae are poorly understood. The central goal of this project is to examine the physiological and molecular basis of metabolic diseases in adults exposed to high levels of glucose only during embryogenesis. To accomplish this goal, we have recently developed a zebrafish model of fetal hyperglycemia. Zebrafish offers several advantages to complete this project. From a biological point of view, zebrafish embryos have the unique feature of being a “closed system” i.e for the first 5 days of development, the embryo solely relies on the yolk sac reserved deposited by the mother during ovulation and no energy exchange happens with the exterior world prior the end of embryogenesis. Therefore, in zebrafish we can directly expose the embryos to known concentration of glucose. Thus, specific aim 1 will test the hypothesis that fetal hyperglycemia leads to an increase in BMI, fat mass and insulin resistance in adults fed normal diet. Specific aim 2 will test the hypothesis that embryonic hyperglycemia increases glycolysis while decreasing 􀈕-oxidation in embryos and in adults. Specific aim 3 will test the hypothesis that fetal hyperglycemia causes hyperlipidemia and non-alcoholic fatty liver disease in adults. Specific aim 4 will test the hypothesis that embryonic hyperglycemia increases the levels of circulating lipids and causes atherosclerosis later in life. Successful completion of this proposal will lead to a better understanding of the physiological and molecular consequences of fetal hyperglycemia and will help in defining strategic therapeutic interventions to prevent the development of metabolic diseases in adults exposed to glucose during embryogenesis.